Phenylcyclopropyl amides



United States Patent 3,192,229 PHENYLCYCLOPROPYL AMIDES John H. Biel,Milwaukee, Wis., assignor to Colgate- Palmolive Company, a corporationof Delaware N0 Drawing. Filed July 3, 1962, Ser. No. 207,424 4 Claims.v(Cl. 260326.3)

This invention relates to novel chemical compounds and processes ofpreparing the same. More particularly, this invention is concerned withamides of phenylcycloproane. p This application is acontinuation-in-part of my copending application Serial No. 105,538filed April 26, 19 6l, now abandoned, and my now abandoned applicatlonSerial No. 11,142 filed February 26, 1960, but which was copending withsaid Serial No. 105,538.

According to the present invention there are provided novelphenylcyclopropyl amides of the formula wherein R can be one or morenuclear substituents such as hydrogen, a lower alkyl such as methyl,ethyl, propyl,

butyl and isopropyl, a lower alkoxy such as methoxy,

ethoxy and propoxy, polyalkoxy groups such as 2,4-

dimethoxy and 2,4,6-trimethoxy, a lower alkylenedioxy suchas3,4-methylenedioxy and 3,4-ethylenedioxy, arylmy groups such as phenoxy,amino, a carboxy-lower alkyl such as carbethoxy, nitro andtrifluoromethyl, R is hydrogen or a lower alkyl (preferably of l-Scarbons) such as methyl or ethyl, and R is hydrogen or a substittuent ofthe group consisting of:

(a) Alkyl groups from 1 to carbons and advisably lower alkyl groups suchas methyl, ethyl, propyl, butyl, isopropyl and the like.

(b) Phenyl containing at least one nuclear substituent such as a halogenlike chlorine, hydroxy, amino, nitro, trifiuoromethyl and lower alkoxy.

(c) Aralkyl groups such as phenyl-lower alkyl groups including thebenzyl, phenethyl, phenylisopropyl and phenylbutyl.

'(d) Cycloalkyl groups such as the cyclopropyl cyclopentyl, andcycloheptyl groups.

' (e) Heterocyclic groups such as pyridyl, pyridyl-lower alkyl, N-loweralkyl piperidyl, N-lower alkyl piperidylloWer alkyl, pyrrolidyl,pyrrolidyl-lower alkyl, N-lower alkyl pyrrolidyl-lower alkyl, indolyland 5-keto-2-pyrrolidyl.

(f) HydroXy-lower alkyl groups such as the hydroxymethyl andhydroxyethyl groups.

(g) Cycloalkyl-lower alkyl groups such as the cyclopentylpropyl andcyclohexylmethyl groups.

(h) Groups in which 0 JLR represents a dicylic glycolyl group includingthe benziloyl, phenylcyclohexyl glycolyl, phenylcyclopentyl glycolyl,2-thieny1 phenyl glycolyl and dicyclohexyl glycolyl groups. Y

(i) Amino-lower alkyl groups such as aminomethyl,

B-aminoethyl, alpha-aminoethyl, 3-(methyl-mercapto)- l-aminopropyl,4-methyl1-aminobutyl, 3-hydroxy-1- aminopropyl,3-methyl-3-hydroxy-l-aminopropyl.

(j) Omega-carboxy-(amino)-lower alkyl groups such asZ-carboxy-l-aminoethyl, i3-carboxy-l-aminopropyl, and

Y 3-carboxy-3-amino-l-propyl.

(k) Carboxyalkylgroups such as the carboxyl-lower alkyl groups includingthe carboxyethyl group. The most important compounds are those of theabove formula in which R is a heterocyclic group such as de- 3,192,229Patented June 29, 1965 fined under (e) above and particularly those inwhich R is a pyrrolidyl or piperidyl group.

The phenylcyclopropylamides are potent inhibitors of the enzyme monamineoXidase. Although phenylcyclo propyl amine is also a potent inhibitor ofthis enzyme, this compound causes a marked increase in blood pres sureand heart rate, as well as an amphetamine-like stimulation of thecentral nervous system. l-Methyl-Z- phenylcyclopropylamine haspharmacological properties quite similar in kind to the compound withoutthe l-methyl group.

The novel phenylcyclopropylamides are practically devoid of undesirableside effects. Furthermore, the acute toxicities of the amides aresignificantly less than for the free amine. This invention thus providespotent inhibitors of the enzyme monoam-ine oxidase which are devoid ofthe concomitant side etfects of the free amine and have much moreselective action in the treatment of the depressed mental state, anginapectoris and arthritis. Clinical improvement in the treatment of thedepressed mental stateis charcterized by elevation of mood, diminutionof confusion, reduction in depressive attitudes and notable alertness.

The phenylcyclopropylamides, other than those from amino acids, can beproduced by reacting a phenylcyclopropylamine as the racemic D,L-miXturewith an appropriate acyl halide in an inert liquid reaction medium suchas benzene, xylene, n-heptane and toluene. Approximately equimolaramounts of reactants can be employed. The reaction proceeds at roomtemperature although elevated temperatures such as the refluxtemperature can be used to increase the reaction rate. An equivalentamount of a strong organic base such as triethylamine can be in: cludedin the reaction mixture to bind the hydrohalic acid released by thereaction. After the reaction is completed, which generally takes no morethan 1 to 3 hours, the reaction mixture can be treated according toconventional manipulative techniques to isolate the desired product.

Z-Phenylcyclopropylamine is disclosed in I. Am. Chem. Soc. 70, 2198 (1948). It is available in the c-is or trans forms, 1 loweralkyl-2-phenylcyclopr-opylamines can also be produced as disclosed inthe prior art. Thus, in J Med. & Pharm. Chem. 4, No. 3, 571 (1961),there is disclosed the preparation of 1-methyl-2-phenylcyclopropylamine.Other compounds of this class in which the methyl group is replaced byethyl, propyl or another lower alkyl can be produced in a similarmanner.

Some of the acyl halides of carboxylic acids which can be used in thisreaction are formyl chloride, acetyl chloride, propionyl chloride,butyryl chloride, isopropionyl bromide, caproyl chloride, caprylbromide, lauroyl chloride, palmityl chloride, benzoyl chloride,o-chlorobenzoyl bromide, 3,4-methylenedioxybenzoyl chloride,p-methoxybenzoyl chloride, phenylacetyl chloride, beta-phenylpropionylchloride, gamma-phenylbutyryl chloride, 3,4- methylenedioxyphenylacetylchloride, cyclopentane car boxyl chloride, cyclohexane carboxylchloride, cyclopentylacetyl chloride, beta-cyclohexyl propionylchloride, benziloyl chloride, and phenylcyclohexyl glycolyl chloride.

Some of the phenycyclopropylamides formed in this way are:

N- 2-phenylcyclopropyl) -formamide N- (Z-phenylcyclopropyl) -acetamideN- (2-phenylcyclopropyl -propionamide N- (2-phenylcyclopropyl)-butyramide N-( 1-methyl-2-phenylcyclopropyl) -acetamide N-Z-phenylcyclopropyl) -p-chloro-benzamide N- (Z-phenylcyclopropyl)-phenylacetamide N- (Z-phenylcyclopropyl -phenylpropionamide N-(2-phenylcyclopropyl -cyclopentyl carboxamide N- (Z-phenylcyclopropyl-cyclohexyl carboxamide (B N- (Z-phenylcyclopropyl -cyclopentylacetamideN- 1-methyl-2-phenylcyclopropyl) -cyclopentylacetamide N-2-phenylcyclopropyl -b eta-cyclohexylpropionamide N-(2-phenylcyclopropyl -benzilamide N- (Z-phenylcycloprpoyl -glycolamide N2-phenylcyclopropyl -beta-hydroxypropion amide N- (2-phenylcyclopropyl-trimethylacetamide N (Z-phenylcyclopropyl -p almitamide The amides ofphenylcyclopropropylamine and aminoacids are advisably prepared byreacting phenylcyclopropylamine with the free amino acid to form theacid addition salt which is dehydrated in situ withdicyclohexylcarbodiimide. This reaction can be represented as follows:

R CH2 R CH in which R is an amino containing group as indicatedpreviously, and R has the significance previously assigned.

A liquid reaction medium is advisably used which dissolves the reactantsbut from which 1,3-dicyclohexylurea, formed in the reaction,precipitates quantitatively. Methanol, ethanol, isopropanol, n-but-anol,dioxane and tetrahydrofuran are typical solvents which can be used forthe reaction medium. The reaction can be effected at room temperature ormoderately elevated temperatures as up to 65 C. -Higher temperatures aregenerally not needed. After the reaction is terminated, the1,3-dicyclohexylurea is removed, as by filtration, and the desired amideisolated by evaporation of the mother liquor.

Representative of the amino acids which can be used in the process areglutamic acid, glycine, serine, 5-methyl-3- isoxazolecarboxylic acid,alanine, tryptophane, aspartic acid, p-chloronicotinic acid,isonicotinic acid, N-methyl nicotinic acid,'methionine, lysine, proline,histidine, N- melthyl-pyrrolidine carboxylic acid and 5-py-rrolidone-2-carboxylic acid (usually as the available L-fo-rm),

- Typical of the phenylcyclopropyl amides which are pro ducedfrom aminoacids are:

N- (2-pheny1cyclopropyl) -5-pyrrolidone-2-carboxamide N-(1-methyl-2-phenylcyclopropyl) -5-pyrrolidone- 2-carboxamide N-(2-phenylcyclopropyl -glutamide N- (Z-phenylcyclopropyl -glycinamide N-2-phenylcyclopropyl) -serinamide N- (2-phenylcyclopropyl)-5-methyl-3-isoxazolecarb oxamide N-( 1-methyl-2-phenylcyclopropyl)-isonicotinamide N- Z-phenylcyclopropyl -alanineamide N-(Z-phenylcyclopropyl) -tryptophanamide N- (2-phenylcyclopropyl-aspartamide N- 2-phenylcyclopropyl -isonicotinamide N-(Z-phenylcyclopropyl) -lysineamide N- (2-phenylcyclopropyl)-methionineamide N- (2-phenylcyclopropyl -pyrrolidine-2-carb oxamide N-(2-phenylcyclopropyl) -nicotin amide Instead of employing racemic2-phenylcyclopropylamine in the described processes this amine can firstbe resolved and the separated D-2-phenylcyclopropylamine or L-2phenylcyclopropylamine, or mixtures. thereof, used to react with theacid or acid halide. The D-form of the amine is more active, so it wouldadvisably be used.

One convenient way to resolve D,L-2-phenylcyclopropylamine is todisperse the amine in the form of an acid addition salt of5-pyrrolidone-Z-carboxylic acid (advisably as the L-form) in ethanol(advisably containing about 5% methanol) and separating the precipitated5-pyrroli done-Z-carboxylic acid addition salt ofL-Z-phenylcyclopropylamine from the mixture leaving the S-pyrrolidone-D-Z-phenylcyclopropylamine can be reacted with L-S-pyrrelidone-Z-carboxylic acid to formD-N-(2-phenylcyclopropyl)-L-5-pyrrolidone-2-carboxa-mide, andL-Z-phenylcyclopropylamine can be reacted with L-S-pyr-rolidone-Z-carboxylic acid to form L-N-(Z-phcnylcyclopropyl)-L-5-pyrrolidone-Z-carboxamide. These products can be mixed togetherinvarious amounts from 0% to 50% of one and 50% to of the other to giveuseful mixtures.

Obviously, if trans-2-phenylcyclopropylamine is resolved, .the opticalisomers will be the trans-isomers.

One of the most active compounds is2-phenylcyclopropyl-5-pyrrolidone-2-carboxarnide which can be used asD,L-N-(Z-phenylcyclopropyl)-5 pyrrolidone 2 carboxamide. However, theoptically activeD-N-(2-phenylcyclopropy-l)-L-5-pyrrolidone-Z-carboxamide has been foundmore. active than the racemic mixture, and to have fewer side effects,.as a monoamine oxidase inhibitor and antidepressant.

The novel amides of this invention are advisably formulated intosuitable pharmaceutical forms. The preferred route of administration isoral and for this method unit dosageforms such as tablets and capsulesare ordinan ily recommended. Unit-dosages can contain any desired amountof the amide although generally 1 to 50 rngm. is suitable. Such dos-agescan be administered one or more at a time once a day or at variousintervalsthroughout the day. Total daily administration of about 1 to100 1 N-trans-2-phenylcyclopropyl-5-pyrrolidone- 2-carboxamide 5 (2)Starch, U.S.'P. 57 (3) Lactose, U.S.P. 73 (4) Talc, U.S.P. -s 9 (5)Stearic acid 6 The following examples illustrate the preparation of thecompounds of this invention:

Example 1 .-N-trans-2-phenylcyclopropyl-L-S- pyrrolidone2-carb0xamide Toa mixture containing 13.3 g. (0.10 mole) of trans-Z-phenylcyclopropylamine and l2.9'g.(0.l0 mole) of L-5-pyrrolidone-Z-carboxylic acid dissolved in cc. of

ethanol were added 21.6 g. (0.105 mole) of dicyclohexylcarbodiimide withcooling. The reaction mixture was solved in 35 cc. of hot.isopropylalcohol.

Example 2.Reslatzon 0f D,L-trans-2-phenylcycl0pr0- pylamine as theL-5-pyrr0lid0ne-2-carboxylic acid salts To a solution of 5.2 g. (0.4mole) of L-S-pyrrolid-one- 2-carboxylic acid in 80 cc. of ethanol with5% methanol at room temperature was added a solution of 5.3 g. (0.4mole) of trans-Z-phenylcyclopropylamine in cc. of ethanol with 5%methanol. The solution was cooled in an ice bath and whencrystallization was complete, the salt was collected by filtration,washed with anhydrous ether and dried, yielding 4.6 g. of salt A, M.P.152-154 C. Recrystallization from acetonitrile afforded 3.8 g. of thepure salt, MJP. 150-15l C. [a] 59.67 (water).

Liberation of the base from salt A with aqueous sodium hydroxide gaverelatively pure L-trans-Z-phenyl-cyclopropylarnine [a] -117.5 (dioxane).

The filtrate remaining after separation of salt A was diluted with etherwhich caused salt B to crystallize affording 4.2 g., MJP. 11812l C.Recrystallization from acetonitrile left 3.9 g. of salt, M.P. 119120 C.'[a] +23.27 (water).

i Liberation of the base from salt B with aqueous sodium hydroxide gavehighly enriched D-trans-2-phenylcyclopropylam'ine, [a] |8l.4 (dioxane).

Example 3.-D-N-(trans-Z-phenylcyciopropyl)-L-5 pyrrolidone-Z-carb0xamideTo a solution of 5.4 g. (0.042 mole) of L-S-pyrrolidone-Z-carboxylicacid and 5.6 g. (0.042 mole) of D- .trans-2-pheny1cyclopropylamine in 35cc. of ethanol with 5% methanol was added a solution of 9.1 g. (0.044mole) of dicyclohexylcarbodiimide in 15 cc. of ethanol with 5% methanol.After stirring overnight at room temperature, the N,N-dicyclohexylurea(9.4 g.) was collected by filtration and was Washed with acetonitrile.The filtrate was concentrated under reduced pressure and the residue(12.9 g.) was dissolved in 15 cc. of warm acetonitrile. Whencrystallization was complete, the solid Was collected by filtration anddried, yielding 7.8 g. of product, M.P. 138141 C. Recrystallization fromhot water left 3.6- g. of amide, M.P. 144- 147 C. [a] 104.28(dimethylformamide) Analysis.Calcd. for C H N O N, 11.47. Found N,11.32.

Example 4.-L-N-(trans-2-phenylcycl0pr0pyl)-L-5-pyrrolidone-Z-carb0xamide A mixture of 7.0 g. (0.054 mole) ofL-5-pyrrolidone Z-carboxylic acid and 7.2 g. ofL-trans-Z-phenylcyclopropylamine (0.054 mole) in 55 cc. of ethanol with5% methanol was treated with 11.5 g. (0.057 mole) ofdicyclohexylcarbodiimide in cc. of ethanol with 5% methanol. Afterstanding overnight at room temperature, the mixture was cooled brieflyin an ice bath and the precipitated urea was'collected by filtration,washed with acetonitrile and dried, yielding 11.2 g. (92%). Anadditional 0.8 g. of urea was obtained from the filtrate by removing thesolvent under reduced pressure and dissolving the residue in 30 cc. ofwarm acetonitrile. On cooling, the urea separated. The filtrate wasconcentrated under reduced pressure and the residue was dis- The desiredamide crystallized on cooling affording a solid, M.P. 129

132 C. Recrystallization from isopropyl alcohol left 4.0

g. of pure amide, M.P. 136-137 C. [oc] -1-1().56 (dimethylformamide) 6Analysis.-Calcd. for C H N O N, 11.47. Found: N, 11.24.

Example 5 .N- (trans-2-phenylcycl0propyl) -p-chlor0- phenoxyacetamide A500 cc. 3 neck round bottom flask was charged with 13.3 g. (0.1 mole) oftrans-phenylcyclopropylamine, 13.8 g. (0.1 mole) of anhydrous potassiumcarbonate and 200 cc. of dry benzene. In approximately 45 minutes, atroom temperature, with stirring was added 20.5 g. (0.1 mole) ofp-chlorophenoxyacetyl chloride in cc. of dry benzene. A voluminous whiteprecipitate formed. After stirring at room temperature for 1 hour, thereaction mixture was refluxed for 3 hours. The precipitate was filteredoff while hot, with a second precipitate falling out in the filtrateupon cooling. The second precipitate was filtered off while cooling andproven to be trans phenylcyclopropylamine hydrochloride. The filtratewas washed with 5% aqueous sodium hydroxide, water, 5% aqueous HCl andWater until neutral. The benzene was removed by distillation. Theresidue of 32.5 g. was picked up in 2-00 cc. of n-hexane. Withscratching and cooling, a precipitate formed. Yield: 16 g. (53%), M.P.83-85 C.

Analysis.Calcd. for C H ClNO: N, 4.64; Cl, 11.77. Found: N, 4.66; CI,12.16.

Example 6 .--N trans-2-phenylcycl0propyl -2-piperidin0 acetamz'deExample 7 .-N (trans-Z-pheny lcyclopropyl -2 -chl0r0- 1 acetamide 6.65g. (0.05 mole) of trans-phenylcyclopropylamine, 50 cc. of anhydrousbenzene and 6.9 g. (0.05 mole) of anhydrous potassium carbonate placedin a 250 cc. 3 neck round bottom flask. The temperature of the mixturewas brought to 010 C. with the aid of an ice bath. 5.65 g. (0.05 mole)of chloroacetyl chloride in 25 cc. of anhydrous benzene was addeddropwise-in 1 hour to the mixture with the temperature being held below10 C. The mixture was stirred at 010 C. for 4 hours and then 1 hour atroom temperature. The precipitate was filtered, washed slowly with 50cc. of ether and then 50 cc. of benzene. The filtrate and washings werecombined and washed successively with 5% NaHCO 5% HCl (aqueous), andwater and the washings discarded. The filtrate was concentrated todryness on a steam bath leaving a solid residue (9g). The residue wasrecrystallized in 100 cc. of warm ether and 50 cc. of n-hexane. Yield:7.6 g. (0.3 g. recovered from mother liquor) 72%, M.P. 7374 C.

Analysis.Calcd. for C H NOClz N, 6.66; Cl, 16.90. Found: N, 6.72; Cl,16.86. I

Example 8 .N trans-2 -plhenylcycl0propyl acry lamid e To a cold solutionof 9.05 g. (0.1 mole) of acryloylchloride in 100 cc. of benzenecontaining a trace of hydroquinone was added in 1 hour dropwise withstirring at 5 10 C. a solution of 13.3 g. (0.1 mole) oftransphenylcyclopropylamine and 10.1 g. (0.1 mole) of tri- Ti heptane.The compound which separated was filtered oit, rinsed with heptane anddried. Yield 15.5 g. (83% M.P. 77 C.

Analysis.Calcd. for C H NO: C, 76.97; H, 7.00; N, 7.48. Found: C, 76.40;H, 6.98; N, 7.52.

Example 9.N-isnic0tin0yl-traits-phenylcyclopropylamine To a solution ofg. (0.2 mole) of isonicotinic acid in 500 cc. of dichloromethane, cooledin ice water, was added 20.3 g. (0.2 mole) of triethylamine. T o theclear solution was added with stirring at 05 C. dropwise, 23.8 g. (0.22mole) ofethylchloroformate. After stirring at 0 C.,for minutes, asolution of 27 g. (0.2 mole) trans-phenylcyclopropylamine in cc.dichloromethane was added dropwise at 0-5 C. The icebath was removed andthe solution was stirred for two hours at room temperature. The solutionwas washed with bicarbonate solution and water, dried and taken todryness to give 40.6 g. residue. This was recrystallized from 50 cc. ofhot. benzene to give 18.9 g. product, M.P. 125 C. After severalrecrystallizations from a four to five-fold amount of ethanol weobtained 4.2 g. of the amide, M.P. 142 C.

Analysis.Calcd. for C H N O: C, 75.61; H, 5.92; N, 11.76. Found: C,75.38; H, 5.96; N, 11.50.

Example 10.N-(4-hydr0xybutyryl) transphenylcyclopropylamine v A'mixtureof 13.3 g. (0.1 mole) trans-phenylcyclopropylamine and 8.6 g. (0.1 mole)vbutyrolactone was heated on a steam bath for 22 hours. The cooledmixture crystallized. The solids were triturated with 50 percentether-n-hexane and filtered. Yield 18.8 g., M.P. 74- 76 C. All solidswere dissolved in 100 ml. warm tetrahydrofuran, filtered, diluted withn-hexane to cloud point and refrigerated. Solids crystallized, collectedby filtration and dried. M.P. 8385 C. 123 g. (56 percent).

Analysis.--Calcd. for C H NO C, 71.20; H, 7.81; N, 6.39. Found: C,69.35; H, 8.27; N, 6.45.

All material recrystallized from 100 ml. hot benzene, cooled, filteredand dried. M.P. 83-85 C. 116 g. (53 percent).

Analysis.--Found: C, 70.27; H, 7.60; N, 6.37.

All solids again recrystallized from 100 ml. hot benzene, filtered,cooled, collected by filtration and dried.

Analysis.--Found: C, 71.50; H, 7.81; N, 6.36.

Example 11 .Trans-N-phenylcyclopropyl-2- (N benzyl-N propargyl aminoacetamide A solution of 21 g. (0.1 mole) of transN-phenylcyclopropyl-Z-chloroacetamide in 150 cc. of toluene was addeddropwise with stirring to a solution of 29 g. (0.2 mole) ofN-benzyl-N-propargylaminein 150 cc. toluene, and,

Example 1 2 .N- (3,4,5-zrimeth0xybenzoyltrans-phenylcyclopropylamine Asolution of 18.5 g. (0.08 mole),of 3,4,5-trimethoxybenzoyl chloridein300 cc.,ether and 50 cc. benzene was added dropwise to a stirredcooled solution of 10.65 g. (0.08 mole) trans-phenylcyclopropylamine,8.1 g. (0.08 mole). triethylamine and 200 cc. ether. The resulting heavywhite precipitate was stirred overnight at room temperature. Theprecipitate was filtered off and SllllTlCd twice in 500 cc. water. Theprecipitate of the final fil- I tration was washed frequently with waterand then dried. Yield 25.5 g., M.P. 178180 C. Recrystallization wasaccomplished from about twenty fold amounts of boiling methanol. Finalyield 18 g. (68 percent), M.P. 192- 194 C.

Analysis.-Calcd. for C H O N: N, 4.25; C, 69.70; H, 6.46. Found: N,4.24; C, 69.86; H, 6.72.

Example 13 .N-trans-2-pheny lcycl0pr0pyl-4- (N-piperidyl) butyramide Toa solution of 8.5 g. (0.1 mole) of piperidine in 200 cc. of benzene wasadded dropwise a solution of 11.9 g. (0.05 mole) ofN-trans-2phenylcyclopropyl-4-chlorobutyramide in cc. of benzene. After24 hours of reflux the salt was filtered OE and the benzene solution wasextracted with dilute aqueous HCl. The aqueous layer was made alkalinewith KOH and was extracted with ether. The ethereal solution was driedover potas sium carbonate, filtered and the ether was removed bydistillation.- The residue was fractionated, yielding 9.8 g. (68.5percent) of base, B.P. 190 C./0.06 mm. N 1.5447.

Analysis.-Calcd. for C H N Oz N, 9.78. N, 9.67. a

Example 14.N-trans-2phenylcyclopropyll chlorobutyramide To a wellstirred mixture ,of 20.7 g. (0.15 mole) of anhydrous potassiumcarbonate, 21.15 g. (0.15 mole) of 4-chlorobutyroylchloride and 300 cc.of dry benzene was added in 1 hour at 10 C. a solution of 20.0 g. (0.15mole) of trans-phenylcyclopropylamine in 100 cc. of henzene. Afterstirring for 4 hours at room temperature, cc. of water was added and thebenzene layer was washed with water, cold dilute HCl and water untilneutral. After drying over anhydrous K CO the benzene Found was removedby distillation leaving .34 g. of a solid residue. This'residue wasdissolved in 350 cc. of ether, filtered and the compound wasreprecipitated by addition of 200 cc. of heptane. 25.5 g. (71.5 percent)of compound, M.P. 74 C. was obtained.

Analysis.-Calcd. for C H ClNO: Cl, 14.92; N, 5.89. Found: Cl, 15.03; N,5.96.

Example 7 15 .-L-p henylalwnyl-d-trans-phenylcyclo- To a cooled mixtureof 29.5 g. (0.1 mole) of carbobenzoxy-L-phenylalanine and 250 cc. ofdichloromethane was added 10.1 g. (0.1 mole) of triethylamine. To thestirred solution was added dropwise at 05 C. a solution of 11.9 g. (0.11mole) of ethylchloroformate in 50 cc. of dichloromethane. The solutionwas kept at 5 C. for 30 minutes, after which a solution of 13.3 g. (0.1mole) of d-trans-phenylcyclopropylarnine in 50 cc. of dichloromethanewas added dropwise at 5 C. The mixture was stirred for 2 hours at roomtemperature, washed with water, bicarbonate solution, dilute HCl, andwater, dried and concentrated to give 38.2 g. of carbobenzoxy-L-phenylalanyl-d trans phenylcyclopropylamine. This crude. amide wasrecrystallized from 275 cc. of hot isopropanol to give 25.5 g. ofproduct, M.P. 150-152 C. Repeated recrystallization from isopropanolincreased the M.P. t 163 C.

Analysis.Calcd. for C H N O N, 6.76. Found: N, 6.77.

A solutionof 8.29 g. ofcarbobenzoxy-l-phenylalanyld-trans-phenylcyclopropylamine in 250 cc. ofethanol was reductively decarbobenzoxylated in the presence of 1 g.

of 10% palladium n carbon catalyst. The catalyst was removed byfiltration, the filtrate was concentrated and mole) ofethylchloroformate.

9 the residue was recrystallized from heptane to give the crystallineamide, M.P. 91 C.

Analysis.Calcd. for C H N N (non aqueous), 4.99; N (total) 10.00. Found:N (non aqueous) 4.87; N (total), 9.98.

Example 1 6 .N -(N -m'ethyl pi pecol'oyl mmo-phenylcyclopropylamine N C6H3 2 To a cooled slurry of 14.3 g. (0.1 mole) of N-methylpipecolic acidin 250 cc. of dichloromethane was added at 20 C., 10.15 g. (0.1 mole) oftriethylamine. To the mixture was added at 5-15 C., dropwise, 11.9 g.(0.11 After the mixture had stirred for 0.75 hours at 5 C., a solutionof 13.3 g. (0.1 mole) of trans-phenylcyclopropylamine in 25 cc. ofdichlorornethane was added in minutes. The resulting clear solution waskept at room temperature for 2 hours, Washed with cold aqueousbicarbonate solution and with water, and finally extracted with dilutehydrochloric acid. The aqueous acid extracts were washed with benzene(discarded) and the solution was made alkaline with potassium hydroxide.The product separated and was extracted into benzene, dried, andevaporated to give 12 g. of oily product, which solidified on standing.The infrared spectrum was consistent with the assigned structure.

Analysis.-Calcd. for C H N O: N, 10.85. Found: N, 10.82.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorpowherein R is a member of thegroup consisting of pyridyl and 5-keto-2-pyrrolidyl and R is a member ofthe group consisting of hydrogen and lower alkyl.

References Cited by the Examiner UNITED STATES PATENTS 2,565,503 *8/51Kaplan 260239.l 2,934,542 4/60 Burger 260340.5 2,951,849 9/60 Gutmann eta1. 260326.3 2,997,422 8/ 6'1 Tedeschi 167--65 3,011,945 12/61 Bollinget a1 167-65 3,068,283 12/62 Kaiser et al. 260326.3

OTHER REFERENCES Fieser and Fieser, Organic Chemistry, 3rd Edition, page270 (1956).

IRVING MARCUS, Primary Examiner.

JOHN D. RANDOLPH, NICHOLAS S. RIZZO,

WALTER A. MODANCE, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,192,229 June 29, 1965 John H. Biel It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1, lines 19 to 23, for that portion of the formula reading 3 read2 line 33, for "substittuent" read substituent column 2, line 21, for"charcterized" read characterized column 3,

line 5, for "Z-phenylcycloprpoyl" read 2-pheny1cyc1opropy1 column 7,line 38, for "123" read 12.3 line 66, for "[3,4,5-trimethoxybenzoyl", initalics, read (3,4,5- trimethoxybenzoyl) in italics Signed and sealedthis 30th day of November 1965.

( L) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. 2-PHENYLCYCLOPROPYL-5-PYRROLIDONE-2-CARBOXAMIDE.
 4. APHENYLCYCLOPROPYL AMIDE OF THE FORMULA